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Radiother Oncol. 2014 Jun;111(3):468-74. doi: 10.1016/j.radonc.2014.04.010. Epub 2014 May 8.

Kinomic exploration of temozolomide and radiation resistance in Glioblastoma multiforme xenolines.

Author information

1
The University of Alabama at Birmingham, USA.
2
Maine Medical Center Research Institute, Portland, USA.
3
The University of Alabama at Birmingham, USA; University of Alexandria, Egypt.
4
Southern Research Institute, Birmingham, USA.
5
The University of Alabama at Birmingham, USA. Electronic address: cwilley@uab.edu.

Abstract

BACKGROUND AND PURPOSE:

Glioblastoma multiforme (GBM) represents the most common and deadly primary brain malignancy, particularly due to temozolomide (TMZ) and radiation (RT) resistance. To better understand resistance mechanisms, we examined global kinase activity (kinomic profiling) in both treatment sensitive and resistant human GBM patient-derived xenografts (PDX or "xenolines").

MATERIALS AND METHODS:

Thirteen orthotopically-implanted xenolines were examined including 8 with known RT sensitivity/resistance, while 5 TMZ resistant xenolines were generated through serial TMZ treatment in vivo. Tumors were harvested, prepared as total protein lysates, and kinomically analyzed on a PamStation®12 high-throughput microarray platform with subsequent upstream kinase prediction and network modeling.

RESULTS:

Kinomic profiles indicated elevated tyrosine kinase activity associated with the radiation resistance phenotype, including FAK and FGFR1. Furthermore, network modeling showed VEGFR1/2 and c-Raf hubs could be involved. Analysis of acquired TMZ resistance revealed more kinomic variability among TMZ resistant tumors. Two of the five tumors displayed significantly altered kinase activity in the TMZ resistant xenolines and network modeling indicated PKC, JAK1, PI3K, CDK2, and VEGFR as potential mediators of this resistance.

CONCLUSION:

GBM xenolines provide a phenotypic model for GBM drug response and resistance that when paired with kinomic profiling identified targetable pathways to inherent (radiation) or acquired (TMZ) resistance.

KEYWORDS:

Array profiling; Glioblastoma; Kinomics; Temozolomide; Xenolines

PMID:
24813092
PMCID:
PMC4119546
DOI:
10.1016/j.radonc.2014.04.010
[Indexed for MEDLINE]
Free PMC Article

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